Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with poor prognosis, wherein muscular atrophy occurs by degeneration and deficit of motor neurons in the spine, motor cortex and brainstem. Familial ALS (Familial Amyotrophic Lateral Sclerosis: FALS) currently accounts for 5-10% of all ALS cases. The responsible gene in some families with FALS has been identified as the Cu/Zn superoxide dismutase (SOD1) gene, with approximately 20% of FALS cases being attributed to genetic mutation in SOD1.
SOD1 inactivates superoxide, an active oxygen species produced in cells during the course of aerobic metabolism. The aggregate theory, which holds that mutated SOD1 forms aggregates in cells and thereby exhibits cellular toxicity, has recently become the prevailing theory as the cause of FALS (Non-patent document 1).
The present inventors have identified NEDL1, a gene coding for E3 ubiquitin ligase having a HECT domain, as a novel gene that is highly expressed in human neuroblastoma groups with good prognosis and natural regression, compared to groups with poor prognosis. It has been demonstrated that NEDL1 has a function of physically binding with mutant SOD1, one of responsible gene products in FALS, inducing its ubiquitination and thus promoting degradation of mutant SOD1. The binding strength between NEDL1 and mutant SOD1 depends on the severity of the condition, while no binding is detected with wild SOD1. In addition, experiments in model mice and immunostaining of actual case patient cells have indicated that ubiquitinated mutant SOD1 and NEDL1 are accumulated in the aggregates. This strongly suggests that interaction between NEDL1 and mutant SOD1 plays an important role in the onset and progression of FALS, although the detailed molecular mechanism of neural cell death (apoptosis) by NEDL1 are still unclear (Patent document 1, Non-patent document 2).    [Patent document 1] International Patent Publication No. WO03/018842    [Non-patent document 1] Rosen DR et al., Nature, 364: 59-62 (1993)    [Non-patent document 2] Miyazaki K et al., J. Biol. Chem., 279: 11327-11335 (2004)